Objective: Determine the neurobiological substrates of GLP-1-mediated food reward suppression by assessing the impact of intramesolimbic Exendin-4 administration on food reward behavior using conditioned place preference and progressive ratio operant-conditioning paradigms
Materials & Equipment Checklist
6 items1 from ConductScience
Gather these items before starting the experiment. Check off items as you prepare.
Equipment2
Not specified • Not specified • Not specified • Not specified
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Protocol Steps
View Abstract
The glucagon-like peptide 1 (GLP-1) system is a recently established target for type 2 diabetes treatment. In addition to regulating glucose homeostasis, GLP-1 also reduces food intake. Previous studies demonstrate that the anorexigenic effects of GLP-1 can be mediated through hypothalamic and brainstem circuits which regulate homeostatic feeding. Here, we demonstrate an entirely novel neurobiological mechanism for GLP-1-induced anorexia in rats, involving direct effects of a GLP-1 agonist, Exendin-4 (EX4) on food reward that are exerted at the level of the mesolimbic reward system. We assessed the impact of peripheral, central, and intramesolimbic EX4 on two models of food reward: conditioned place preference (CPP) and progressive ratio operant-conditioning. Food-reward behavior was reduced in the CPP test by EX4, as rats no longer preferred an environment previously paired to chocolate pellets. EX4 also decreased motivated behavior for sucrose in a progressive ratio operant-conditioning paradigm when administered peripherally. We show that this effect is mediated centrally, via GLP-1 receptors (GLP-1Rs). GLP-1Rs are expressed in several key nodes of the mesolimbic reward system; however, their function remains unexplored. Thus we sought to determine the neurobiological substrates underlying the food-reward effect. We found that the EX4-mediated inhibition of food reward could be driven from two key mesolimbic structures—ventral tegmental area and nucleus accumbens—without inducing concurrent malaise or locomotor impairment. The current findings, that activation of central GLP-1Rs strikingly suppresses food reward/motivation by interacting with the mesolimbic system, indicate an entirely novel mechanism by which the GLP-1R stimulation affects feeding-oriented behavior.
1
Peripheral Exendin-4 Administration and CPP Testing
Administer Exendin-4 peripherally and assess impact on food-reward behavior using conditioned place preference test with chocolate pellets as reward stimulus
Not specifiedNot specified
Conditioned Place Preference - Mouse (Custom Order)
Matches: Conditioned Place Preference (CPP) apparatus
Note: This establishes baseline effect of EX4 on food reward
View evidence from paper
“Food-reward behavior was reduced in the CPP test by EX4, as rats no longer preferred an environment previously paired to chocolate pellets”
2
Peripheral Exendin-4 Administration and Progressive Ratio Testing
Administer Exendin-4 peripherally and measure motivated behavior for sucrose using progressive ratio operant-conditioning paradigm
Not specifiedNot specified
Note: Demonstrates EX4 effect on food motivation
View evidence from paper
“EX4 also decreased motivated behavior for sucrose in a progressive ratio operant-conditioning paradigm when administered peripherally”
3
Central Exendin-4 Administration
Administer Exendin-4 centrally to determine if food-reward suppression is mediated through central GLP-1 receptors
Not specifiedNot specified
Note: Establishes central mediation of EX4 effects via GLP-1 receptors
View evidence from paper
“We show that this effect is mediated centrally, via GLP-1 receptors (GLP-1Rs)”
4
Intramesolimbic Exendin-4 Administration - Ventral Tegmental Area
Administer Exendin-4 directly into the ventral tegmental area and assess effects on food reward behavior
Not specifiedNot specified
Note: Identifies ventral tegmental area as a key mesolimbic substrate for EX4-mediated food reward suppression
View evidence from paper
“We found that the EX4-mediated inhibition of food reward could be driven from two key mesolimbic structures—ventral tegmental area and nucleus accumbens”
Administer Exendin-4 directly into the nucleus accumbens and assess effects on food reward behavior
Not specifiedNot specified
Note: Identifies nucleus accumbens as a key mesolimbic substrate for EX4-mediated food reward suppression without inducing malaise or locomotor impairment
View evidence from paper
“We found that the EX4-mediated inhibition of food reward could be driven from two key mesolimbic structures—ventral tegmental area and nucleus accumbens—without inducing concurrent malaise or locomotor impairment”
